The compound, 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]-amino]-2-propanol is known as Carvedilol. Carvedilol is depicted by the following chemical structure:

Carvedilol is disclosed in U.S. Pat. No. 4,503,067 to Wiedemann et al. (i.e., assigned to Boehringer Mannheim, GmbH, Mannheim-Waldhof, Fed. Rep. of Germany), which was issued on Mar. 5, 1985.
Currently, carvedilol is synthesized as free base for incorporation in medication that is available commercially. The aforementioned free base form of Carvedilol is a racemic mixture of R(+) and S(−) enantiomers, where non-selective β-adrenoreceptor blocking activity is exhibited by the S(−) enantiomer and α-adrenergic blocking activity is exhibited by both R(+) and S(−) enantiomers. Those unique features or characteristics associated with such a racemic Carvedilol mixture contributes to two complementary pharmacologic actions: i.e., mixed venous and arterial vasodilation and non-cardioselective, beta-adrenergic blockade.
Carvedilol is used for treatment of hypertension, congestive heart failure and angina. The currently commercially available carvedilol product is a conventional, tablet prescribed as a twice-a-day (BID) medication in the United States.
Carvedilol contains an α-hydroxyl secondary amine functional group, which has a pKa of 7.8. Carvedilol exhibits predictable solubility behaviour in neutral or alkaline media, i.e. above a pH of 9.0, the solubility of carvedilol is relatively low (<1 μg/mL). The solubility of carvedilol increases with decreasing pH and reaches a plateau near pH=5, i.e. where saturation solubility is about 23 μg/mL at pH=7 and about 100 μg/mL at pH=5 at room temperature. At lower pH values (i.e., at a pH of 1 to 4 in various buffer systems), solubility of carvedilol is limited by the solubility of its protonated form or its corresponding salt formed in-situ. For example, a hydrochloride salt of carvedilol generated in situ an acidic medium, which simulates gastric fluid, is less soluble in such medium.
In addition, the presence of the α-hydroxyl secondary amine group in the Carvedilol chemical structure confers a propensity upon the compound to chemically react with excipients normally included in a dosage form to aid manufacture, maintain quality, or enhances dissolution rate. For example, the α-hydroxyl secondary amine group of Carvedilol can react with aldehydes or ester functional groups through nucleophilic reactions. Common chemical functional group residues associated with conventionally used excipients, include ester, aldehyde and/or other chemical residue functional groups. This often results in marginal or unacceptable chemical stability upon storage.
In light of the foregoing, novel salt forms of carvedilol with greater aqueous solubility, chemical stability, etc. would offer many potential benefits for provision of medicinal products containing the drug carvedilol.
Such benefits would include products with the ability to achieve desired or prolonged drug levels in a systemic system by sustaining absorption along the gastrointestinal tract of mammals (i.e., such as humans), particularly in regions of neutral pH, where a drug, such as carvedilol, has minimal solubility.
Surprisingly, it has now been shown that novel crystalline forms of carvedilol salts, may be isolated as a pure crystalline solid, which exhibit much higher aqueous solubility than the corresponding free base or other prepared crystalline carvedilol salts.
This novel crystalline form also has potential to improve the stability of carvedilol in formulations due to the fact that the secondary amine functional group attached to the carvedilol core structure, a moiety pivotal to degradation processes, is protonated as a salt.
In light of the above, a need exists to develop different carvedilol salt forms and/or different corresponding compositions, respectively, which have greater aqueous solubility, chemical stability, sustained or prolonged drug or absorption properties (i.e., such as in neutral gastrointestinal tract pH regions, etc.).
There also exists a need to develop methods of treatment for cardiovascular diseases and/or associated disorders, which may include, but are not limited to hypertension, congestive heart failure or angina, etc., which comprises administration of the such carvedilol salt forms, and/or corresponding pharmaceutical compositions.
The present invention is directed to overcoming these and other problems encountered in the art.